Enhanced Skin Permeation of a New Capsaicin Derivative (DA-5018) from a Binary Vehicle System Composed of Isopropyl-myristate and Ethoxydiglycol

  • Published : 2001.06.01

Abstract

DA-5018, a recently synthesized capsaicin analog, appears to possess potent analgesic activity when administered topically. The objective of this study is to test the feasibility of the topical administration of this compound. Specifically, our goal was to identify vehicle system that permit a reasonable transdermal permeation of the compound in mice. Among the vehicles examined, isopropyl myristate (IPM) showed the largest in vitro permeability across the intact skin (83.6 ${\pm}$ 5.42${\mu}$l/$\textrm{cm}^2$/h ). However, due to the limited solubility of DA-5018 in IPM (0.53 mg/ml), the maximal flux from the IPM medium remained at only 44.3 ${\pm}2.87{\mu}$g/$\textrm{cm}^2$/hr. In order to increase the flux, addition of better solvents for DA-5018 was attempted, under the assumption that flux is the result of both solubility and permeability. Ethoxydiglycol (EG) and oleic acid (OA) were selected as examples of food solvents. The addition of IC or OA to IPM at a 1:1 volume ratio resulted in a comparable increase in the solubility of the compound (i.e., to 61.1 and 50.2 mg/ml for EG and OA, respectively). However, the addition of EG at a 1:1 volume ratio, for example, increased the flux 6.3 fold (i.e., $279{\mu}$g/$\textrm{cm}^2$/hr), while OA, at a 1:1 volume ratio, decreased the flux 5 fold (i.e., $9.26{\mu}$g/$\textrm{cm}^2$//hr). The mechanism of this discrepancy between EG and OA was investigated by measuring the permeabilty of DA-5018 across the stratum corneum-removed skin of the mouse, under the hypothesis that the viable skin layer may serve as a barrier for the permeation of lipophilic substances such as DA 5018. The permeability of DA-5018, from the medium of EG or OA, across the viable skin differed greatly for EG ($0.41{\mu}$l/$\textrm{cm}^2$/hr) and OA ($0.086{\mu}$l/$\textrm{cm}^2$/hr), suggesting that a higher permeability across the viable skin layer is needed for the second solvents. The maximum flux across the intact skin was achieved for DA-5018 when EG was added to IPM at a 1:1 volume ratio. Thus, the use of a binary system appears to be the best approach for realizing the transdermal delivery of DA-5018 at a reasonable rate.

Keywords

References

  1. J. Pharm. Pharmacol. v.37 Correlation of thermodynamic activity and vapor diffusion through human skin for the model compound, benzyl alcohol Barry,B.W.;Harrison,S.M.;Dugard,P.H.
  2. J. Pharm. Pharmacol. v.37 Optimization of bioavailability of topical steroids: non-occluded penetration enhancers under thermodynamic control Bennet,S.L.;Barry,B.W.;Woodford,R.
  3. Ph. D. Thesis, College of Pharmacy, Seoul National University Formulation study of cream for a new capsaicin derivative, N-3-(3,4-dimethylphenyl)propyl]-4-(2-aminoethoxy)-3-methoxy phenyl acetamide Cha,B.J.
  4. A double-blind trial. Clin. Ther. v.13 Treatment of arthritis with topical capsaicin Chad,L.D.;Thomas,J.S.;Esther,L.;James,R.S.;Randall,M.S.;Moise,D.L.;Daniel,A.;Frederic,R.
  5. J. Cont. Rel. v.18 In vitro skin permeation technique David,R.F.
  6. Int. J. Pharm. v.28 A method of predicting percutaneous absorption from vehicle to vehicle: An experimental assessment Dugard,P.H.;Scott,R.C.
  7. J. Pharm. Sci. v.61 Membrane diffusion Ⅲ: Influence of solvent composition and penetrant solubility on membrane transport Flynn,G.L.;Smith,R.W.
  8. J. Pharm. Pharmacol. v.25 no.SUP. The effect of thermodynamic activity on the percutaneous absorption of methyl nicotinate from water glycerol mixtures Hadgraft,J.;Hadgraft,J.W.;Sarkany,L.
  9. N. Engl. J. Med. v.14 Topical capsaicin in the treatment of painful diabetic neuropathy Levy,D.M.;Abraham,R.R.;Tomlinson,D.R.
  10. Korean J. Med. Chem. v.1 N-Aralkylated 4-(2-aminoethoxy) phenyl-acetamide derivatives as potent analgesic and antiinflammatory agents Park,N.S.;Ha,D.C.;Choi,J.K.;Kim,H.S.;Lim,H.J.;Lee,B.Y.
  11. J. Chromatogr. Determination of a new non-narcotic analgesic, DA-5018, in plasma, urine and bile by high-performance liquid chromatography Shim,H.J.;Lee,J.J.;Lee,S.D.;Kim,W.B.;Yang,J.;Kim,S.H.;Lee,M.G.
  12. J. Appl. Pharmacol. v.5 Analgesic effects of DA-5018, a new capsaicin derivative, against experimental acute pain Son,M.H.;Bae,E.J.;Kim,H.K.;Shin,M.S.;Kim,S.H.;Kim,W.B.;Yang,J.;Park,N.S.
  13. Diabetes Care v.15 Topical capsaicin in painful diabetic neuropathy: Controlled study with long-term follow-up Tandan,R.;Lewis,G.A.;Krusinski,P.B.;Fries,T.J.
  14. Clin. Ther. v.15 A randomized vehicle-controlled trial of topical capsaicin in the treatment of post therapeutic neuralgia Watson,C.P.;Tylor,L.K.;Bickers,D.R.;Millican,L.E.;Smith,S.;Coleman,E.